Transforming cisplatin therapy: a localized, injectable poly(anhydride-ester) depot for safer and more effective head and neck cancer treatment.

Abstract

Head and neck cancer patients often receive systemic cisplatin chemotherapy, which is effective but limited by severe toxicity and poor tumor selectivity. An injectable, biodegradable polyanhydride polymer derived from sebacic acid (SA) and ricinoleic acid (RA) was investigated as a localized carrier for cisplatin to improve its safety and efficacy. Cisplatin was loaded into a poly(SA-RA) polymer at 1% and 10% (w/w) concentrations. The 10% formulation ("TumoCure") was evaluated for safety and pharmacokinetics via subcutaneous administration in rats and intramuscular administration in pigs. Efficacy was assessed using a diluted 1% cisplatin formulation, administered intratumorally in a FaDu human head-and-neck squamous cell carcinoma xenograft model in mice. In vitro studies demonstrated sustained cisplatin release from the polymer over several weeks, a release profile that correlated well with in vivo kinetics and followed an apparent first-order pattern. In the mouse tumor model, intratumoral injection of the 1% polymer-cisplatin formulation produced dose-dependent tumor growth inhibition with prolonged local drug activity. In contrast, systemic cisplatin administration resulted in early tumor regrowth and significant toxicity. The polymer-based treatment caused no observable systemic toxicity or weight loss, with only localized, transient tissue reactions noted at the injection sites. The cisplatin-loaded poly(SA-RA) matrix provides controlled release and enhanced local efficacy in head and neck tumor models, with minimal systemic side effects supported by a tenfold reduction in systemic drug exposure. These results support the potential of this injectable, biodegradable polymer formulation as a safer and more effective alternative to systemic cisplatin for patients with locally advanced head and neck carcinoma, particularly those who are unfit for or have contraindications to systemic chemotherapy.